Trauma and Genomics Modulate Brain Structure across Common Psychiatric Disorders
Trauma and Genomics Modulate Brain Structure across Common Psychiatric Disorders
批准号:
9389397
负责人:
MARK W LOGUE
金额:
$47.07万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-06 至 2021-07-31
关键词:
AdultAmygdaloid structureAnxiety DisordersArchitectureAreaArousalAutomobile DrivingBehaviorBig DataBioinformaticsBipolar DisorderBrainChildChildhoodClinical PathsCollaborationsCorpus striatum structureDataDiseaseEnvironmentEvaluationExposure toExtinction (Psychology)FrightGene ExpressionGenesGeneticGenetic MarkersGenetic Predisposition to DiseaseGenetic VariationGenomicsGenotypeGoalsHeritabilityHippocampus (Brain)HumanIndividualInterventionLeadLifeMagnetic Resonance ImagingMeasuresMedialMemoryMental DepressionMental disordersMeta-AnalysisMethodologyMolecularMolecular GeneticsMood DisordersMorphologyNeurobiologyParticipantPathogenesisPathologyPathway interactionsPhenotypePost-Traumatic Stress DisordersPsychopathologyResearch Domain CriteriaRiskRisk FactorsSamplingShapesSiteStructureSurfaceSymptomsThickTraumaabuse neglectbasebrain pathwayclinical phenotypedeep sequencingendophenotypegene discoverygenetic risk factorgenetic variantgenome wide association studyinattentionneuroimagingnew therapeutic targetpediatric traumapsychogeneticspsychological traumatoolwhite matterwhole genomeworking group
中文摘要
摘要
儿童期是神经发育的关键时期,遭受创伤和虐待是一个主要的危险因素。
成人精神病病理科。然而,并不是所有受到童年创伤的儿童都会长大成人。
精神变态学。创伤相关病理风险的变异性预计在一定程度上是由于遗传
敏感度。最近发现了几个基因,它们与儿童创伤相互作用,从而增加了发病率
成年后的焦虑和情绪障碍。通过检查可以更容易地检测到这种风险
内表型,如从MRI获得的大脑测量,因为更简单的潜在基因
具有比驱动总体风险的多种因素更少的单个基因或途径的架构
精神变态学。了解分子遗传学对大脑结构的贡献
早期生活环境(心理创伤)并导致成人精神病理,将需要大规模
利用大数据方法的协作努力。我们的目标是进行一次相关的全球气候变化
对儿童时期遭受创伤的个体进行结构性大脑测量,长期目标是确定
大脑结构的遗传调节剂,对一系列疾病的早期预测和治疗具有重要意义
童年创伤是主要危险因素的精神障碍。我们假设(1)童年创伤
将与特定的遗传标记相互作用,产生结构性的大脑变化和成人的精神病理,
(2)在儿童创伤遗传易感性的背景下,独特的遗传变异将影响
出现特定疾病(例如,抑郁症与创伤后应激障碍),以及(3)特定症状的出现
跨障碍的结构(例如,持续威胁)。发现与疾病相关的基因变异,指向
由于临床表型的多样性,发病的分子机制已被证明是具有挑战性的。
利用神经成像表型可能提供一种比临床表型更直接的方法来识别
这些难以捉摸的遗传标记和相关的神经生物学途径。最终,找到基因的希望
任何精神障碍的贡献者都是在识别其存在的新的生物路径时
可以设计和部署有针对性的干预措施。
英文摘要
ABSTRACT
Exposure to trauma and abuse during childhood, a critical neurodevelopmental period, is a major risk factor
for adult psychopathology. However, not all children exposed to childhood trauma will develop adult
psychopathology. Variability in the risk for trauma-related pathology is expected to arise in part from genetic
susceptibility. Several genes have recently been identified that interact with childhood trauma to increase rates
of anxiety and mood disorders in adulthood. This risk can be more easily detected by examining
endophenotypes such as brain measures obtained from MRI because of a simpler underlying genetic
architecture with fewer individual genes or pathways than the multiple factors driving overall risk for
psychopathology. Understanding the molecular-genetic contributors to brain structure that conspire with
early-life environment (psychological trauma) and lead to adult psychopathology, will require large-scale
collaborative efforts which harness big-data methodologies. Our goal is to conduct a GWAS of relevant
structural brain measures in individuals exposed to childhood trauma, with the long-term goal of identifying
genetic modulators of brain structure that are informative for early prediction and treatment for a range of
psychiatric disorders where childhood trauma is a major risk factor. We hypothesize that (1) childhood trauma
will interact with specific genetic markers to produce structural brain alterations and adult psychopathology,
(2) that unique genetic variants, in the context of genetic vulnerability to childhood trauma, will influence the
onset of specific disorders (e.g. depression vs PTSD), as well as (3) the presentation of specific symptom
constructs (e.g. sustained threat) across disorders. Finding disease-associated genetic variation that point to
molecular mechanisms of pathogenesis has proven challenging due to the polygenicity of clinical phenotypes.
Leveraging neuroimaging phenotypes may offer a more direct path than clinical phenotypes in identifying
these elusive genetic markers and relevant neurobiological pathways. Ultimately, the promise of finding genetic
contributors of any psychiatric disorder is in identifying the presence of new biologic pathways for which
targeted interventions may be devised and deployed.
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会议论文
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